1. Field of the Invention
The present invention relates to tricarbonyl technetium-99m or rhenium-188 labeled cyclic RGD derivatives, a preparation method thereof, and a pharmaceutical composition containing the derivatives as an active ingredient for use in the diagnosis or treatment of angiogenesis-related disease.
2. Description of the Related Art
The nuclear medicine diagnosis and treatment technologies, which are capable of noninvasive technique for a disease at molecular level using radiotracers with specificity to target molecules, is considered important more than ever because the current medicinal field has a main goal of complete cancer treatment.
The positron emission tomography (PET) is generally used for the diagnosis of cancer in vivo, using radiopharmaceutical such as [18F]-FDG(2-fluoro-deoxy-D-glucose). However, [18F]-FDG is not possible to diagnose of brain tumor, or distinguish between inflammation and tumor, and also has a limitation that it cannot provide information about angiogenesis and symptoms of metastasis.
Angiogenesis is indispensable in the primary or metastatic tumor. Tumor tissues do not grow more than 1-2 mm3 without supply of nutrients and oxygen from the new vessels. That is, angiogenesis leads to formation of metastatic cancer at other sites through blood vessels during neovascularization. Accordingly, imaging for targeting of new vessels has a potential to be applied commonly for most of solid tumor. In terms of treatment, the conventional chemotherapy focuses on the rapid growth of cancer cells, and thus displays toxicity to normal cells including bone marrow cells and gastrointestinal cells. Compared to the above, a treatment (radiotherapy) targeting angiogenesis brings in relatively less side-effect associated with prolonged administration, and less risk of developing a tolerance because the treatment focuses on vascular cells.
As well known, the growth mechanism of cancer begins as vessels near the cancer tissues have over of αvβ3 integrin. Integrin is heterodimer membrane protein consisting of α and β submits involved with adhesion or transport of the cells. Among various types of integrins, integrin αvβ3, also called vitronectin receptor, is considered important in the angiogenesis. This particular integrin does not express in normal vascular endothelial cells, because the integrin expresses only when tumor-triggered angiogenesis is activated. The Arg-Gly-Asp (RGD) peptide sequence is commonly known for binding with this integrin. Based on this sequence, cyclic Arg-Gly-Asp (cRGD) peptide compound is reported to be an antagonist having higher binding affinity to block normal function of integrin αvβ3, and many research groups have been carried out for imaging of cancer angiogenesis worldwide, by introducing a variety of radioisotopes in this particular compound.
Radioisotopes such as fluorine-18, gallium-68 and copper-64 for PET, and technetium-99m, iodine-123, and indium-111 for SPECT have been used in various cyclic RGD derivatives, added with monosaccharide to enhance pharmacokinetics of the radiotracer, or added with dimeric or tetrameric cyclic RGD to further enhance binding affinity (Haubner, R., Wester, H-J., Weber, W. A., Mang, C., Ziegler, S. I., Goodman, S. L., Senekowi tsch-Schmidtke, R., Kessler, H., Schwa iger, M. Cancer Res., 2001, 61:1781-1785; Jeong, J. M., Hong, M. K., Chang, Y. S., Lee Y. S., Kim, Y. J., Cheon, G. J., Lee, D. S., Chung, J. K., Lee, M., J. Nucl Med., 2008, 49:830-836; Chen, W., Park, R., Tohme, M., Shahinian, A. H. Bading, J. R., Cont i, P. S. Bioconjugate Chem., 2004, 15:41-49; Liu, S., Hsieh W. Y., Kim, Y. S., Mohammel, S. I., Bioconjugate Chem., 2005, 16:1580-1588 Haubner, R., Wester, H-J., Reuning, U., Senekowitsch_Schmidtke, R. Diefenbach, B., Kessler, H., Stocklin G., Schwa iger, M., J. Nucl. Med., 1999 40:1061-1071; Jans sen, M., Oyen, W. J. G., Dijkgraaf, I., Massuger, L. F. A. G. Friel ink, C., Edwards, D. S., Rajo adyhe, M., Boonstra, H., Corsten, F. H. M. Boerman, O., Cancer Res., 2002, 62:6146-6151; Wu, Y., Zhang, X., Xiong, Z. Cheng, Z., Fisher, D. R., Liu, S., Gambhir, S. S., Chen, X., J. Nucl. Med. 2005, 46: 1707-1718). Despite the various radioisotope labeled cyclic RGD derivatives developed so far, the shortcomings such as high accumulation in liver and slow excretion from large intestines still keep as a radiotracer for diagnosis with limited efficiency due to low accumulation ratio between tumor and normal tissues. Further, climical researches have not been made actively yet, especially, in case of radiotherapy, because the therapeutic radioisotope labeled radiotracers can effects on not only tumor but also normal tissues in the radiotherapy.
Among various radioisotopes, technetium-99m and rhenium-188 are considered outstanding in practical aspect, because diagnoses is enabled through single photon emission computed tomography (SPECT) simple labeling method and separating processes, while requiring only a generator. Further, it is possible to selectively label rhenium-188 using the same precursor for the purpose of radiotherapy.
However, the conventional method of labeling technetium-99m and rhenium-188 has shortcomings such as large pocket size to label of technetium-99m or rhenium-188, low in vivo stability, and difficult precursor synthesis, which in turn limit development of efficient radiotracers in many ways. Meanwhile, tricarbonyl technetium-99m and tricarbonyl rhenium-188 are acceptable for as the efficient radiotracers considering characteristics such as easy precursor synthesis, and small and metabolic stable labeling pocket, and it is also possible to change the charge of radiotracer in the preparation process sith a simple change. Furthermore, these radiotracers have a good in vivo stability and rapid clearance without being accumulated at the thyroid at a metabolism, enabling relatively better imaging result. Use of tricarbonyl technetium-99m or tricarbonyl rhenium-188 is not extensively known, but under continuous researches worldwide for the development of new radiopharmaceuticals.
Accordingly, the present inventors synthesize novel tricarbonyl technetium-99m or rhenium-188 labeled cyclic RGD derivatives for targeting integrin αvβ3, a prime biomarker, for imaging and radiotherapy of cancer angiogenesis, and completed the present invention after confirming through various biological evaluations that the tricarbonyl technetium-99m or rhenium-188 labeled RGD derivatives are capable of diagnosing and treating various diseases related with angiogenesis.